The present invention relates to processes for the preparation of phosphatides and salts thereof in general. In particular, the present invention relates to processes for the preparation of specific phospholipids starting from standard natural phospholipids that are reacted in the presence of a water-insoluble stationary surfactant-matrix material.
Specific phospholipids such as phosphatidylserine, phosphatidic acid, and some phosphatidylglycerols are used in pharmaceutical compositions, nutritional compounds, and functional foods.
The importance of phosphatidylserine as a functional ingredient was demonstrated in 2003 when the US FDA allowed two qualified health claims in which the usage of phosphatidylserine was related to the reduction of cognitive-dysfunction risk and dementia in the elderly.
In the prior art, Hellhammer et al. (“Effects of Soy Lecithine Phosphatidic Acid and Phosphatidylserine Complex (PAS) on the Endocrine and Psychological Responses to Mental Stress,” Stress, The International Journal on the Biology of Stress, Vol. 7, No. 2, 119-126, June, 2004) reported that the oral administration of phosphatidic acid and phosphatidylserine complex resulted in a dampening effect of the pituitary adrenal reactivity (ACTH, cortisol) and the psychological response (Spielberger's State-Trait Anxiety Inventory (STAI) stress subscale) to mental and emotional stress. The results indicated that the oral administration of phosphatidic acid and phosphatidylserine complex can be used as a treatment of stress-related disorders.
Eibl et al describe the “Preparation of phospholipids analogs by phospholipase-D” (“Methods in Enzymology,” Vol. 72, pages: 632-639, 1981).
De Ferra et al., in U.S. Pat. No. 6,492,146 (hereinafter De Ferra '146), disclose a process for the preparation of phosphatidylserine with racemic or enantiomerically pure serine (i.e. (L)-serine) in the presence of the enzyme phospholipase-D (PLD) and a surfactant in a quantity not greater than 0.4 grams per gram of substrate in which the reaction medium is an aqueous dispersion free of organic solvents. According to De Ferra '146, the main advantage of the process is the possibility to carry out the transphosphatidylation reaction of phosphatidylcholine, and of similar phosphatides in an aqueous medium, to obtain phosphatidylserine of good purity with highly-satisfactory yields and with minimal phosphatidic acid by-product.
Typically, a solvent is used to completely dissolve the lecithin in such reactions. A dissolved solution, as opposed to a suspension, makes the process easier to manage.
Basheer, in WO Patent Publication No. 2000/056869 (hereinafter Basheer '869), discloses a process of preparing for inter- and/or trans-esterification of oils and fats in hydrophobic organic media using an insoluble matrix-immobilized surfactant-coated-lipase complex as a biocatalyst. The preparation of the insoluble matrix-immobilized surfactant-coated lipase complex includes, in any desired order, the steps of: contacting a lipase with a surfactant, and contacting the lipase with an insoluble matrix at a concentration to obtain immobilization of the lipase on the matrix.
Basheer et al., in WO Patent Publication No. 2002/090560 (hereinafter Basheer '560), disclose an enzyme-catalyzed synthetic process for the production of glycerophospholipids and their synthetic or natural analogues. The process provides an enzymatic esterification/transesterification (acylation) process for the production of 1,2-diacylated and 1-acylated-2-lysophospholipids using glycerophosphorylcholine (GPC) as a substrate or analogue derivatives in which the choline moiety can be substituted by ethanolamine, serine, inositol, glycerol, or any other alcohol, together with a fatty-acid derivative. The reaction can be performed in a solvent, or in a solvent-water system in which a microaqueous sub-system is generated, and in the presence of a phospholipase which may be non-immobilized and surfactant-coated, or preferably, immobilized onto an insoluble matrix, and optionally surfactant-coated (modified). The process leads to the formation of 1-acyl-2-lyso-glycerophospholipids and 1,2-di-acylated glycerophospholipids with a high conversion rate.
Rutenberg, in U.S. Pat. No. 6,410,522 (assigned to the assignee of the present invention and hereby incorporated by reference as if fully set forth herein), teaches an anti-depressant, stress suppressor, and mood improver having a prominent action for decreasing blood cortisol level and serotonin reuptake, and has an effect of alleviating symptoms associated with depression and mental & emotional stress of a subject administered with the improver.
It would be desirable to have processes for the preparation of phosphatides and salts thereof in which the reaction is carried out in a non-solvent, aqueous medium in the presence of a water-insoluble stationary surfactant-matrix material acting as a catalyst in which the process enables the production and separation of phosphatides with no need for further costly extraction of surfactant material from the reaction mixture with solvents.